Biology subjects

Zimmerman, A.

Publications and source records attributed to Zimmerman, A..

6 recordsLinked to original sources

bioRxiv2026

miR-34/449 miRNAs regulate choroid plexus ciliogenesis to control cerebrospinal fluid production

A developmental increase in cerebrospinal fluid (CSF) production during development is essential for neuronal growth and ventricular expansion. A key regulator of CSF production is the specialized sensory multicilia of the choroid plexus (ChP), which mediate non-canonical Sonic hedgehog (Shh) signaling to suppress water channel and ion transporter expression, thereby limiting CSF production. ChP multicilia progressively shortens during development, attenuating Shh signaling and promoting CSF production. Here, we identify miR-34/449 miRNAs as essential regulators of ChP multiciliogenesis. Whereas mutations in canonical ciliogenesis genes elevate CSF production and contribute to hydrocephaly, deletion of miR-34/449 reduces CSF volume and causes microcephaly. Loss of miR-34/449 miRNAs causes excessive basal body amplification, defective basal body docking, and failure of developmental multiciliary shortening. Consequently, miR-34/449-deficient ChP cilia remain abnormally long and fail to attenuate Shh signaling, resulting in sustained repression of water channel and ion transporter expression and reduced CSF production. Mechanistically, miR-34/449 miRNAs directly target Gmnc, a master transcriptional regulator of multiciliogenesis, to restrain basal body amplification and promote basal body docking. Together, our findings identify miR-34/449 miRNAs as critical regulators of ChP multiciliogenesis and establish the developmental remodeling of ChP multicilia as a mechanism to couple Shh signaling dynamics to developmental control of CSF production.

developmental biology↗

bioRxiv2025

Multicilia dynamically transduce Shh signaling to regulate choroid plexus functions

Choroid plexus is a major site for cerebrospinal fluid (CSF) production, characterized by a multiciliated epithelial monolayer that regulates CSF production. We demonstrate that defective choroid plexus ciliogenesis or Intraflagellar transport yields neonatal hydrocephalus, at least in part, due to increased water channel Aqp1 and ion transporter Atp1a2 expression. We demonstrate choroid plexus multicilia as sensory cilia, transducing both canonical and non-canonical Shh signaling. Interestingly, it is the non-canonical Shh signaling that represses Aqp1 and Atp1a2 expression by Smo/Gi/cAMP pathway. Choroid plexus multicilia exhibit unique ciliary ultrastructure, carrying features of both primary and motile cilia. Unlike most cilia that elongate during maturation, choroid plexus ciliary length decreases during development, causing a decline of Shh signaling intensity in developing choroid plexus, a derepression of Aqp1 and Atp1a2, and ultimately, an increased CSF production. Hence, developmental dynamics of choroid plexus multicilia dampens the Shh signaling intensity to promote CSF production.

developmental biology↗

bioRxiv2024

Improving the visualization of viruses in soil

Viruses are numerically the most abundant forms on Earth, and most are present in soil. Even though viruses are highly abundant in soil and critical to rhizosphere function, visualizing the diverse morphotypes within soil has been challenging. The difficulty is primarily due to the heterogenous nature of isolated suspensions that typically contain nanometer to micron scale debris which renders protein crystallography for structural studies unfeasible and hinders cryo-electron microscopy due to ice thickness and contrast issues. Here we employed and compared a simple spin filtration method to cleanup solutions of extracted viruses for direct observation with cryo-electron microscopy. Although relatively simple, the method employs common physical biochemical separation steps to remove large and small debris which dramatically improves image quality and preservation of structural features to permit visualizing morphotypes not typically seen with conventional negative stain approaches. In addition to tailed and non-tailed polyhedral phages, several under reported or novel morphotypes of soil viruses are directly visualized as a particle library with both 2D and 3D information.

microbiology↗

bioRxiv2024

Iron limitation differentially affects viral replication in key marine microbes

Viral lysis accounts for much of microbial mortality in the ocean, and iron (Fe) is a critical micronutrient that can limit phytoplankton growth, yet interactions between Fe-nutrition and viral lysis are not well known. Here, we present viral infection dynamics under Fe-limited and Fe-replete conditions for three distinct marine microbes, the photosynthetic picoeukaryote Ostreococcus lucimarinus, the cyanobacterium Synechococcus, and two strains of the heterotrophic bacterium Vibrio. Iron limitation of Ostreococcus resulted in slowed growth, and a corresponding decrease in viral burst sizes was observed; this is similar to results from studies of larger eukaryotic phytoplankton (Slagter et al. 2016; Kranzler et al. 2021), where reduced viral replication under Fe-limitation is attributed to the viral reliance on host metabolism and replication machinery. For one strain of Vibrio, Fe-limitation similarly impacted viral dynamics, increasing the latent period before infected cells burst to release new virus, and reducing the number of infective viral particles released upon viral lysis. Unexpectedly, for another strain of Vibrio, Fe-limitation had no discernible effect on viral replication. Furthermore, dynamics of three Synechococcus cyanophages was not affected by Fe-limitation of the host, either in terms of latent period or burst size. The results illuminate the extraordinary ability of some marine viruses, particularly cyanophages, to highjack host metabolism to produce new viral particles, even when host growth is compromised. This has implications for marine ecology and carbon cycling in Fe-limited regions of the global ocean.

microbiology↗

bioRxiv2021

Variant-to-gene-mapping followed by cross-species genetic screening identifies GPI-anchor biosynthesis as novel regulator of sleep

Sleep is nearly ubiquitous throughout the animal kingdom, with deficiencies in sleep having been linked to a wide range of human disorders and diseases. While genome wide association studies (GWAS) in humans have identified loci robustly associated with several heritable diseases or traits, little is known about the functional roles of the underlying causal variants in regulating sleep duration or quality. We applied an ATAC-seq/promoter focused Capture C strategy in human iPSC-derived neural progenitors to carry out a variant-to-gene mapping campaign that identified 88 candidate sleep effector genes connected to relevant GWAS signals. To functionally validate the role of the implicated effector genes in sleep regulation, we performed a neuron-specific RNAi screen in the fruit fly, Drosophila melanogaster. This approach identified a number of genes that regulated sleep, including phosphatidylinositol N-acetylglucosaminyltransferase subunit Q (PIG-Q), a gene that encodes an enzyme involved in the first step of glycosylphosphatidylinositol (GPI)- anchor biosynthesis. We show that flies deficient for PIG-Q have longer sleep during both day and night due to an increase in the total number of sleep bouts. Subsequent systematic investigation of other PIG-family genes identified increased sleep in flies for multiple different genes within the PIG pathway. We then mutated the PIG-Q locus in zebrafish and identified similar increases in sleep to those observed in Drosophila, confirming deep homology of PIG-Q mediated sleep regulation. These results provide the first physical variant-to-gene mapping of human sleep genes followed by a model organism-based prioritization, revealing a novel and conserved role for GPI-anchor biosynthesis in sleep regulation.

genetics↗

bioRxiv2019

Biodistribution and inflammatory response of intracranial delivery of scintillating nanoparticles

Nanoparticle-based delivery systems have become a popular method for targeting tumors and impermeable tissue with drugs for treatment and imaging markers for biodetection. Nanomaterials are beneficial for medical treatment because they can be modified to have increased stability and carrying capacity, and their size and surface modifications allow them to reach otherwise impenetrable tissue. Localized or systemic injection can be used for delivery of nanoparticles; however, systemic injection without appropriate surface modifications is subjected to uptake by the mononuclear phagocytic system which clears particles from the circulation rapidly limiting their accumulation at target tissue and reducing efficacy. Here we demonstrate the biodistribution of Yttrium oxyorthosilicate nanoparticles doped with Cerium after localized injection to the cerebral cortex as well as the immune response at the site of injection over time.

bioengineering↗